Allylic alkylations form an important class of reactions in synthetic organic chemistry (Trost et al. (2002) Chem. Pharm. Bull. (Tokyo) 50:1–14; Hayashi et al. (1988) J. Org. Chem. 53: 113–120; Trost et al. (1997) J. Am. Chem. Soc. 119: 7879–7880; Sugimoto et al. (1997) J. Org. Chem. 62: 2322–2323; Satoshi et al, (2003) Chirality 15: 68–70). The unique reactivity of compounds containing allylic groups accounts for their utility in synthetic transformations and multi-step syntheses. Although numerous methods exist for adding allyl groups onto compounds displaying a variety of structures and functional groups, current limitations have generated much effort towards expanding the scope of the transformation.
A well-established approach towards allylic alkylation is via simple nucleophilic substitution. Under basic conditions, alcohols, amines and carbanion precursors such as malonates form nucleophiles that react with alkyl halides or triflates to form the corresponding O—, N— or C-alkylated products. As an example of this method, allylic alkylation of these nucleophilic substrates can be achieved using allyl halides. Regio- and stereocontrol over the alkylation product, however, is highly dependent upon the structure of the reactant.
An important subset of allylation reactions in general is the formation of α-allyl ketones. Allylation of allyl-enol carbonates is one approach toward this goal. As originally described (Tsuji et al. (1987) Acc. Chem. Res. 20: 140–145; Tsuji et al. (1983) Tetrahedron Lett. 24: 1793–1796; Tsuji et al. (1985) J. Org. Chem. 50: 1523–1529; Tsuji et al. (1983) Chem. Lett. 12: 1325–1326), a palladium catalyst is used in conjunction with a phosphine ligand such as PPh3. The reaction proceeds via decarboxylative degradation of the starting material to form, in situ, an electrophilic allyl moiety and a nucleophilic enolate. The reaction affords excellent regiocontrol, and occurs under essentially neutral conditions. Unfortunately, the allylation reported by Tsuji et al. displays no stereocontrol; the reaction results in a racemic mixture of α-allylcyclohexanone products. As a result of the lack of stereocontrol, this approach has since been used and reported as a synthetic tool only sparingly.
Synthetic methods for preparing α-quaternary carbons are generally more useful when the products are enantioenriched. Enantioselectivity has been achieved in allylation reactions for a limited pool of substrates using a Palladium catalyst in conjunction with chiral ligands. These systems have been essentially confined to allylation of β-diketones and β-ketoesters using prochiral electrophiles, or to α-aryl ketones and cyclic ketones that can only form a single enolate (Hayashi et al. (1988) J. Org. Chem. 53: 113–120; Sawamura et al., (1992) J. Am. Chem. Soc. 114: 2586–2592; Trost et al. (1997) J. Am. Chem. Soc. 119: 7879–7880; Kuwano, et al. (1999) J. Am. Chem. Soc. 121: 3236–3237; Trost et al. (1999) J. Am. Chem. Soc. 121: 6759–6760; You et al. (2001) Org. Lett. 3: 149–151; Trost et al. (2002) Angew. Chem. Int. Ed. 41: 3492–3495). In general, strongly basic conditions are required in order to form the reactive enolate intermediate. For example, Trost et al. (2002) describes the allylation of α-aryl ketones using the strongly basic reagents lithium diisoproplyamide or sodium 1,1,1,3,3,3-hexamethyldisilazide. Hayashi et al. described the enantioselective allylation of β-diketones using a palladium catalyst, while Trost et al. (1997) has shown similar results for β-ketoester substrates. Sugimoto et al. used chromium(III) complexes in order to catalyze enantioselective allylation reactions of aldehydes. Titanium(IV) catalysts were used by Satoshi et al. in order to enantioselectively allylate certain ketones.
In light of the limited success in developing enantioselective allylation reactions, there exists a need in the art for a method to prepare highly enantioenriched α-quaternary cycloalkanones and related compounds via enantioselective allylation. Such a method would, optimally, tolerate of a wide variety of functional groups on the substrate, require mild reaction conditions, and employ readily available catalyst/ligand systems. Also desirable is the ability to carry out the reaction on a broad range of structurally distinct compounds. Flexibility in the choice of the catalyst system is also highly desirable.